Principle Investigator: Stephen Waggoner, PhD

Stephen Waggoner.Kawasaki disease is an acute systemic vasculitis and leading cause of pediatric heart disease in developed countries. Worldwide incidence ranges from 10 to 265 cases per 100,000 children under 5 years of age. One in four untreated patients, and even one in 20 patients treated with high-dose intravenous pooled human IgG, will develop potentially fatal coronary artery aneurysms. Giant coronary artery aneurysms (≥8mm) represent an extreme discordant phenotype that can lead to heart attack and death. There is a decisive gap in our understanding of factors contributing to coronary artery aneurysms that must be overcome to improve prognosis and treatment of this disease. We recently discovered a mutation in the EPX gene encoding eosinophil peroxidase (EPO) in two unrelated Kawasaki disease patients who developed giant coronary artery aneurysms during acute disease. As expression of EPO is tightly restricted to eosinophils, this finding suggests that eosinophils play a previously unrecognized role in the development of coronary artery aneurysms in Kawasaki disease.

We will use patient cells, eosinophil cell lines, and induced pluripotent stem cell-derived eosinophils to determine the effects of this EPX change on eosinophil development and function, as well as its influence on coronary aneurysm formation in Kawasaki disease. Finally, we will determine that EPX mutations or other eosinophil-related genetic lesions are a common feature of patients with giant coronary artery aneurysms. This research will help us to understand the mechanisms of EPX and eosinophil contributions to Kawasaki disease, development of new therapies to prevent coronary artery aneurysms formation, and advancement of clinical tests for better prognosis of coronary artery aneurysms risk in febrile patients with suspected Kawasaki disease.